(A) U.S. Pat. No. 4,390,534, issued June 28, 1983 to Tsutomu Teraji et al., discloses cephem and cepham compounds of the formula ##STR3## wherein R.sup.1 is amino or protected amino; R.sup.2 is hydrogen, acyl, optionally substituted aryl, substituted alkyl, alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkenyl or an O- or S-containing 5-membered heterocyclic ring substituted with oxo group(s); R.sup.3 is hydrogen or alkyl; R.sup.4 is hydrogen, acyloxyalkyl, acylthioalkyl, optionally substituted pyridinioalkyl, optionally substituted heterocyclylthioalkyl, alkyl, halogen, hydroxy or optionally substituted thiazolioalkyl; and R.sup.5 is carboxy or protected carboxy; provided that R.sup.5 is COO.sup.- when R.sup.4 is optionally substituted pyridinioalkyl or optionally substituted thiazolioalkyl; and the dashed line indicates either a single or double bond.
European Patent Application No. 13,762, published Aug. 6, 1980 is concordant thereto and has a similar disclosure.
U.S. Pat. Nos. 4,381,299 (issued Apr. 26, 1983), 4,331,665 (issued May 25, 1982) and 4,332,798 (issued June 1, 1982) each issued on parent applications of U.S. Pat. No. 4,390,534, and have similar disclosures.
(B) European Patent Application No. 62,321, published Oct. 13, 1982, discloses cephem compounds of the formula ##STR4## wherein R.sup.1 is amino or protected amino; R.sup.2 is an optionally substituted lower aliphatic hydrocarbon group, or cycloalkenyl; and the group of the formula ##STR5## is an optionally substituted heterocyclic cation group containing more than one nitrogen atom; and pharmaceutically acceptable salts thereof. Also disclosed are intermediates of the formula ##STR6## wherein R.sup.1 and R.sup.2 are as defined above, R.sup.4 is a protected carboxyl group and X.sup.- is an acid residue.
(C) European Patent Application No. 74,653, published Mar. 23, 1983, discloses cephem compounds of the formula ##STR7## wherein
R.sup.1 is amino or protected amino;
R.sup.2 is an optionally substituted lower aliphatic hydrocarbon group, cyclo(lower)alkyl or cyclo(lower)alkenyl;
R.sup.3 is (lower)alkylamino, N-protected(lower)alkylamino, di(lower)alkylamino, sulfo(lower)alkylamino, hydroxy(lower)alkylamino, N-protected hydroxy(lower)alkylamino, acyloxy(lower)alkyl, (lower)alkoxy(lower)alkoxy(lower)alkyl, di(lower)alkylamino(lower)alkyl, (lower)alkylthio(lower)alkyl, (lower)alkylthio, (lower)alkoxy, (lower)alkoxy(lower)alkoxy, hydroxy(lower)alkoxy, acyl(lower)alkyl, hydroxy(lower)alkylthio, di(lower)alkylamino(lower)alkylthio, N-containing unsaturated 5-membered heterocyclic group, N-containing unsaturated 5-membered heterocyclicthio, or N-containing unsaturated 5 or 6-membered heterocyclicthio(lower)alkyl which may be substituted with suitable substituent(s); and
R.sup.4 is hydrogen or (lower)alkyl; or a salt thereof.
(D) U.S. Pat. No. 4,332,800, issued June 1, 1982 to Tsutomu Teraji et al., discloses inter alia compounds of the formula ##STR8##
wherein R.sup.1 is amino or protected amino; R.sup.2 is (lower)alkyl and X is hydrogen or carbamoyl.
(E) European Patent Application No. 47,977, published Mar. 24, 1982, discloses cephem compounds of the formula ##STR9## wherein m is 0 or 1; Am is optionally substituted amino; T is a thiadiazolyl moiety (attached to the other groups by two of its carbon atoms); R.sub.2 is hydrogen, optionally substituted alkyl, cycloalkyl or optionally substituted carbamoyl; and R.sub.1 is optionally substituted thiazolio, optionally substituted pyrazolio, tri(lower)alkylammonio or a pyridinio group of the formula ##STR10## in which R.sup.a is substituted (lower)alkyl [the substituent being cycloalkyl, phenyl, hydroxy, alkoxy, halogen, cyano, carbamoyl, carboxyl or sulfo], (lower)alkenyl or carboxy-substituted (lower)alkenyl, (lower)alkylthio or carboxy-substituted (lower)alkylthio, amino or monosubstituted amino [the substituent being(lower)alkyl, (lower)alkanoyl or aminobenzenesulfonyl], di(lower)alkylamino, substituted carbamoyl [the substituent being (lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy, hydroxy or cyano], di(lower)alkylcarbamoyl, thiocarbamoyl, cycloalkyl, phenyl, hydroxy, (lower)alkoxy, halogen, (lower)alkoxycarbonyl, (lower)alkanoyloxy, (lower)alkanoyl, carboxyl, sulfo, cyano, nitro or hydroxysulfo(lower)alkyl; R.sup.b is hydrogen or carbamoyl, or has the same meaning as R.sup.a ; and R.sup.c is hydrogen or has the same meaning as R.sup.a ; and salts thereof.
Although not formally related, European Patent Application No. 25,017, published Mar. 11, 1981, has a similar disclosure.
(F) European Patent Application No. 30,630, published June 24, 1981, discloses 3-vinyl cephem compounds of the formula ##STR11## wherein R.sup.1 is an optionally protected amino-substituted heterocyclic group which may also have halogen, or a group of the formula ##STR12## in which R.sup.3 is (lower)alkyl; R.sup.2 is carboxy or protected carboxy; and A is lower alkylene which may have a substituent selected from amino, protected amino, hydroxy, oxo and a group of the formula .dbd.N.about.OR.sup.4, wherein R.sup.4 is hydrogen, cyclo(lower)alkenyl, (lower)alkynyl, (lower)alkenyl [optionally substituted by carboxy or protected carboxy], (lower)alkyl [optionally substituted by one or more of carboxy, protected carboxy, amino, protected amino, cyano, phosphono, protected phosphino and a heterocyclic group which itself may be substituted]; and salts thereof.
This application specifically discloses compounds of the formula ##STR13## in which OR.sup.4 is methoxy, carboxymethoxy, tert-butoxycarbonylmethoxy or 1-tert-butoxycarbonylethoxy.
(G) U.K. Patent Specification No. 1,399,086 published June 25, 1975, contains a generic disclosure encompassing a vast number of cephalosporins of the formula ##STR14## wherein R is hydrogen or an organic group, R.sup.a is an etherifying monovalent organic group linked to the oxygen through a carbon atom, B is &gt;S or &gt;S.fwdarw.O, and P is an organic group. In one embodiment, P may be inter alia a vinyl group of the formula ##STR15## in which R.sup.3 and R.sup.4 independently may be hydrogen, nitrile, (lower)alkoxycarbonyl, or substituted or unsubstituted aliphatic, cycloaliphatic, araliphatic or aromatic. However, the 5-amino-1,2,4-thiadiazol-3-yl group is not identified as a possible R substituent and there is no disclosure or suggestion that P may be a quaternary ammonio-substituted propenyl group. U.S. Pat. No. 3,971,778 and its divisionals Nos. 4,024,133, 4,024,137, 4,064,346, 4,033,950, 4,079,178, 4,091,209, 4,092,477 and 4,093,803 have similar disclosures.
(H) European Patent Application No. 88,385, published Sept. 14, 1983, discloses compounds of the formula ##STR16## in which R.sup.1 is (unsubstituted) thiadiazolyl; R.sup.2 is carboxy(lower)alkyl or protected carboxy(lower)alkyl; R.sup.3 is hydrogen, halogen or (lower)alkenyl; and R.sup.4 is carboxy or protected carboxy. Although 1-propenyl is listed as one of the possible meanings of R.sup.3, the application only exemplifies compounds where R.sup.3 is hydrogen, chloro or vinyl.
(I) U.S. Pat. No. 4,307,233 issued to Daniel Farge et al. on Dec. 22, 1981, discloses inter alia, 3-vinylcephalosporin derivatives of the formula ##STR17## in which R.sup.5 inter alia may be alkyl, vinyl, cyanomethyl or a protective group such as 2-methoxyprop-2-yl, and R.sup.3 and R.sup.4 are alkyl groups (optionally substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups, or R.sup.3 and R.sup.4, taken together with the nitrogen to which they are attached, may form a saturated heterocyclic ring of 5 or 6 members, optionally containing another hetero-atom selected from N, O and S, and optionally substituted by an alkyl group. The compounds are useful as intermediates in the preparation of 3-thiovinyl cephalosporin derivatives. There is no disclosure or suggestion of a 5-amino-1,2,4-thiadiazol-3-yl moiety in place of the 2-aminothiazol-4-yl substituent or of a quaternary ammonio-substituted propenyl moiety for the 3-substituent. Published U.K. Patent Application No. 2,051,062 is concordant thereto and has a similar disclosure.
(J) European Patent Application No. 53,537, published June 9, 1982, discloses, inter alia, 3-vinylcephalosporin derivatives of the formula ##STR18## in which R.sub.5.sup.a and R.sub.5.sup.b are the same or different and are hydrogen or alkyl, or taken together, form an alkylene group containing 2 or 3 carbon atoms, R.sub.5.sup.c is an acid protecting group, R.sub.2 is an acid protecting group such as an ester, R.sub.3 and R.sub.4 are the same or different and are hydrogen, alkyl (optionally substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups, or R.sub.3 and R.sub.4, taken together with the nitrogen to which they are attached, may form a saturated heterocyclic ring of 5 or 6 members, optionally containing another hetero-atom selected from N, O and S, and optionally substituted by an alkyl group. The compounds are useful as intermediates in the preparation of 3-thiovinyl cephalosporin derivatives. There is no disclosure or suggestion of a 5-amino-1,2,4-thiadiazol-3-yl moiety in place of the 2-aminothiazol-4-yl substituent or of a quaternary ammonio-substituted propenyl group for the 3-substituent.
U.S. Pat. No. 4,423,214 is concordant thereto and has a similar disclosure.
(K) European Patent Application No. 53,074, published June 2, 1982, generically discloses a vast number of 3-vinylcephalosporin derivatives of the formula ##STR19## wherein R.sub.1a .degree. (in one of several embodiments) may be ##STR20## in which R.sub.5 inter alia may be hydrogen, alkyl, vinyl, cyanomethyl, an oxime-protecting group such as trityl, etc., or a group of the formula ##STR21## in which R.sub.5.sup.a and R.sub.5.sup.b are the same or different, and may be hydrogen, alkyl or, taken together, an alkylene radical of 2 or 3 carbon atoms, and R.sub.5.sup.c is hydrogen or an acid-protecting radical;
R.sub.2a .degree. is hydrogen or an acid-protecting radical such as methoxymethyl;
R.degree. (in one of several embodiments) may be a methyl group substituted by a 5- or 6-membered aromatic heterocyclic ring containing a single hetero atom, such as 2- or 3-pyridyl, 2- or b 3-thienyl or 2- or 3-furyl; and
R.sub.3 is a group of the formula EQU R.sub.4 SO.sub.2 O--
in which R.sub.4 may be alkyl, trihalomethyl or optionally substituted phenyl.
These compounds are stated to be intermediates in the preparation of compounds in which the 3-substituent is a group of the formula ##STR22## which are stated to have antibacterial activity.
Although this patent includes the possibility of R.degree. being a methyl group substituted by an N-containing heterocyclic ring, in both the intermediates and final products (thus giving a heterocyclic-substituted propenyl moiety), it teaches only that the heterocyclic ring is attached via one of its carbon atoms. Thus, there is no suggestion of a quaternary ammonio-substituted propenyl group. The reference exemplifies R.degree. in the intermediates and final products only as methyl. Further, in both the intermediates and final product, the propenyl group must contain a second substituent (--O.sub.3 SR.sup.4 or --SR, respectively). Also there is no disclosure or suggestion of a 5-amino-1,2,4-thiadiazol-3-yl moiety in place of the 2-aminothiazol-4-yl substituent.
(L) European Patent Application No. 53,538, published June 9, 1982, discloses, inter alia, 3-vinylcephalosporin intermediates of the formula ##STR23## in which n is 0 or 1, R.sup.5 is hydrogen, alkyl, vinyl, cyanomethyl or an oxime-protecting group, and R.sup.3 is halogen. There is no disclosure or suggestion of a 5-amino-1,2,4-thiadiazol-3-yl moiety in place of the 2-aminothiazol-4-yl substituent, and no disclosure or suggestion of a 3-halo-1-propen-1-yl substituent in the 3-position.